The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 receptor (ORL=Opioid-Receptor-Like)(Meunier et al., Nature 377, 1995, pp 532-535), which belongs to the family of the opioid receptors, is found in many regions of the brain and spinal cord and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide has a strong similarity to those of the known opioid peptides. The receptor activation induced by nociceptin leads to an inhibition of adenylate cyclase via coupling with Gi/o proteins (Meunier et al., Nature 377, 1995, pp 532-535).
After intercerebroventricular administration, the nociceptin peptide displays a pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, pp 792-794). These findings can be explained as an inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, pp 333-337). In this connection it has also been possible to detect an anxiolytic activity of nociceptin (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand, it has also been possible to show an antinociceptive effect of nociceptin in various animal models, especially after intrathecal administration. Nociceptin has an antinociceptive action in various pain models, for example in the mouse tail flick test (King et al., Neurosci. Lett. 223, 1997, 113-116). In neuropathic pain models, it has likewise been possible to detect an antinociceptive action of nociceptin which is of particular interest inasmuch as the efficacy of nociceptin increases after the axotomy of spinal nerves. This is in contrast to the classical opioids, whose efficacy decreases under these conditions (Abdulla and Smith, J. Neurosci. 18, 1998, pp 9685-9694).
The ORL1 receptor also participates in the regulation of other physiological and pathophysiological processes. These include, inter alia, learning and memorization (Manabe et al., Nature 394, 1997, pp 577-581), hearing acuity (Nishi et al., EMBO J. 16, 1997, pp 1858-1864) and numerous other processes. A survey by Calo et al. (Br. J. Pharmacol. 129, 2000, 1261-1283) gives a summary of the indications or biological processes in which the ORL1 receptor plays or very probably might play a role. The following are mentioned, inter alia: analgesia, stimulation and regulation of ingestion, effect on μ agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy, modulation of the release of neurotransmitters, especially glutamate, serotonin and dopamine, and hence neurodegenerative diseases, influence on the cardiovascular system, triggering of an erection, diuresis, antinatriuresis, electrolyte metabolism, arterial blood pressure, water retention diseases, intestinal motility (diarrhoea), relaxing effects on the respiratory tract, and micturition reflex (urinary incontinence). Said survey further discusses the use of agonists and antagonists as anoretics, analgesics (also in coadministration with opioids) or nootropics.
The possible applications of compounds that bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse. Apart from this receptor, opioid receptors such as the μ receptor and other subtypes play a major role in the precise area of pain therapy, but also in other indications among those mentioned. Accordingly, it is advantageous if a compound is also active at these opioid receptors.